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1 Clinical effectiveness and cost-effectiveness of body psychotherapy in the treatment of negative symptoms of schizophrenia: a multicentre randomised controlled trial Article (Published Version) Priebe, Stefan, Savill, Mark, Wykes, Til, Bentall, Richard, Lauber, Christoph, Reininghaus, Ulrich, McCrone, Paul, Mosweu, Iris, Bremner, Stephen, Eldridge, Sandra and Röhricht, Frank (2016) Clinical effectiveness and cost-effectiveness of body psychotherapy in the treatment of negative symptoms of schizophrenia: a multicentre randomised controlled trial. Health technology assessment (Winchester, England), 20 (11). pp ISSN This version is available from Sussex Research Online: This document is made available in accordance with publisher policies and may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher s version. Please see the URL above for details on accessing the published version. Copyright and reuse: Sussex Research Online is a digital repository of the research output of the University. Copyright and all moral rights to the version of the paper presented here belong to the individual author(s) and/or other copyright owners. To the extent reasonable and practicable, the material made available in SRO has been checked for eligibility before being made available. Copies of full text items generally can be reproduced, displayed or performed and given to third parties in any format or medium for personal research or study, educational, or not-for-profit purposes without prior permission or charge, provided that the authors, title and full bibliographic details are credited, a hyperlink and/or URL is given for the original metadata page and the content is not changed in any way.

2 HEALTH TECHNOLOGY ASSESSMENT VOLUME 20 ISSUE 11 FEBRUARY 2016 ISSN Clinical effectiveness and cost-effectiveness of body psychotherapy in the treatment of negative symptoms of schizophrenia: a multicentre randomised controlled trial Stefan Priebe, Mark Savill, Til Wykes, Richard Bentall, Christoph Lauber, Ulrich Reininghaus, Paul McCrone, Iris Mosweu, Stephen Bremner, Sandra Eldridge and Frank Röhricht on behalf of the NESS team DOI /hta20110

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4 Clinical effectiveness and cost-effectiveness of body psychotherapy in the treatment of negative symptoms of schizophrenia: a multicentre randomised controlled trial Stefan Priebe, 1* Mark Savill, 1 Til Wykes, 2 Richard Bentall, 3 Christoph Lauber, 4 Ulrich Reininghaus, 2,5 Paul McCrone, 6 Iris Mosweu, 6 Stephen Bremner, 7 Sandra Eldridge 8 and Frank Röhricht 1 on behalf of the NESS team 1 Unit for Social and Community Psychiatry, World Health Organization Collaborative Centre for Mental Health Services Development, Queen Mary University of London, London, UK 2 Institute of Psychiatry, Psychology and Neuroscience, King s College London, London, UK 3 Department of Psychiatry, University of Liverpool, Liverpool, UK 4 Services Psychiatriques Jura bernois, Bienne-Seeland, Bellelay, Switzerland 5 Department of Psychiatry and Psychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands 6 Centre for the Economics of Mental and Physical Health, Institute of Psychiatry, Psychology and Neuroscience, King s College London, London, UK 7 Division of Primary Care and Public Health, Brighton and Sussex Medical School, Brighton, UK 8 Centre for Primary Care and Public Health, Queen Mary University of London, London, UK *Corresponding author Declared competing interests of authors: Stefan Priebe is a member of Health Technology Assessment (HTA) Mental, Psychological & Occupational Health Panel. Til Wykes and Ulrich Reininghaus report grants from King s College London. Sandra Eldridge is a member of the HTA Clinical Evaluation and Trials Board and reports grants from Queen Mary University of London. Frank Röhricht has a copyright pending on the body psychotherapy schizophrenia manual (Röhricht F. Body-oriented Psychotherapy in Mental Illness: A Manual for Research and Practice. Goettingen: Hogrefe; 2000). Published February 2016 DOI: /hta20110

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6 This report should be referenced as follows: Priebe S, Savill M, Wykes T, Bentall R, Lauber C, Reininghaus U, et al. Clinical effectiveness and cost-effectiveness of body psychotherapy in the treatment of negative symptoms of schizophrenia: a multicentre randomised controlled trial. Health Technol Assess 2016;20(11). Health Technology Assessment is indexed and abstracted in Index Medicus/MEDLINE, Excerpta Medica/EMBASE, Science Citation Index Expanded (SciSearch ) and Current Contents / Clinical Medicine.

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8 Health Technology Assessment HTA/HTA TAR ISSN (Print) ISSN (Online) Impact factor: Health Technology Assessment is indexed in MEDLINE, CINAHL, EMBASE, The Cochrane Library and the ISI Science Citation Index. This journal is a member of and subscribes to the principles of the Committee on Publication Ethics (COPE) ( Editorial contact: nihredit@southampton.ac.uk The full HTA archive is freely available to view online at Print-on-demand copies can be purchased from the report pages of the NIHR Journals Library website: Criteria for inclusion in the Health Technology Assessment journal Reports are published in Health Technology Assessment (HTA) if (1) they have resulted from work for the HTA programme, and (2) they are of a sufficiently high scientific quality as assessed by the reviewers and editors. Reviews in Health Technology Assessment are termed systematic when the account of the search appraisal and synthesis methods (to minimise biases and random errors) would, in theory, permit the replication of the review by others. HTA programme The HTA programme, part of the National Institute for Health Research (NIHR), was set up in It produces high-quality research information on the effectiveness, costs and broader impact of health technologies for those who use, manage and provide care in the NHS. Health technologies are broadly defined as all interventions used to promote health, prevent and treat disease, and improve rehabilitation and long-term care. The journal is indexed in NHS Evidence via its abstracts included in MEDLINE and its Technology Assessment Reports inform National Institute for Health and Care Excellence (NICE) guidance. HTA research is also an important source of evidence for National Screening Committee (NSC) policy decisions. For more information about the HTA programme please visit the website: This report The research reported in this issue of the journal was funded by the HTA programme as project number 08/116/68. The contractual start date was in May The draft report began editorial review in June 2015 and was accepted for publication in October The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors report and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report. This report presents independent research funded by the National Institute for Health Research (NIHR). The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Health. If there are verbatim quotations included in this publication the views and opinions expressed by the interviewees are those of the interviewees and do not necessarily reflect those of the authors, those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Health. Queen s Printer and Controller of HMSO This work was produced by Priebe et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. Published by the NIHR Journals Library ( produced by Prepress Projects Ltd, Perth, Scotland (

9 Health Technology Assessment Editor-in-Chief Professor Hywel Williams Director, HTA Programme, UK and Foundation Professor and Co-Director of the Centre of Evidence-Based Dermatology, University of Nottingham, UK NIHR Journals Library Editor-in-Chief Professor Tom Walley Director, NIHR Evaluation, Trials and Studies and Director of the HTA Programme, UK NIHR Journals Library Editors Professor Ken Stein Chair of HTA Editorial Board and Professor of Public Health, University of Exeter Medical School, UK Professor Andree Le May Chair of NIHR Journals Library Editorial Group (EME, HS&DR, PGfAR, PHR journals) Dr Martin Ashton-Key Consultant in Public Health Medicine/Consultant Advisor, NETSCC, UK Professor Matthias Beck Chair in Public Sector Management and Subject Leader (Management Group), Queen s University Management School, Queen s University Belfast, UK Professor Aileen Clarke Professor of Public Health and Health Services Research, Warwick Medical School, University of Warwick, UK Dr Tessa Crilly Director, Crystal Blue Consulting Ltd, UK Dr Peter Davidson Director of NETSCC, HTA, UK Ms Tara Lamont Scientific Advisor, NETSCC, UK Professor Elaine McColl Director, Newcastle Clinical Trials Unit, Institute of Health and Society, Newcastle University, UK Professor William McGuire Professor of Child Health, Hull York Medical School, University of York, UK Professor Geoffrey Meads Professor of Health Sciences Research, Health and Wellbeing Research and Development Group, University of Winchester, UK Professor John Norrie Health Services Research Unit, University of Aberdeen, UK Professor John Powell Consultant Clinical Adviser, National Institute for Health and Care Excellence (NICE), UK Professor James Raftery Professor of Health Technology Assessment, Wessex Institute, Faculty of Medicine, University of Southampton, UK Dr Rob Riemsma Reviews Manager, Kleijnen Systematic Reviews Ltd, UK Professor Helen Roberts Professor of Child Health Research, UCL Institute of Child Health, UK Professor Jonathan Ross Professor of Sexual Health and HIV, University Hospital Birmingham, UK Professor Helen Snooks Professor of Health Services Research, Institute of Life Science, College of Medicine, Swansea University, UK Professor Jim Thornton Professor of Obstetrics and Gynaecology, Faculty of Medicine and Health Sciences, University of Nottingham, UK Please visit the website for a list of members of the NIHR Journals Library Board: Editorial contact: nihredit@southampton.ac.uk NIHR Journals Library

10 DOI: /hta20110 HEALTH TECHNOLOGY ASSESSMENT 2016 VOL. 20 NO. 11 Abstract Clinical effectiveness and cost-effectiveness of body psychotherapy in the treatment of negative symptoms of schizophrenia: a multicentre randomised controlled trial Stefan Priebe, 1* Mark Savill, 1 Til Wykes, 2 Richard Bentall, 3 Christoph Lauber, 4 Ulrich Reininghaus, 2,5 Paul McCrone, 6 Iris Mosweu, 6 Stephen Bremner, 7 Sandra Eldridge 8 and Frank Röhricht 1 on behalf of the NESS team 1 Unit for Social and Community Psychiatry, World Health Organization Collaborative Centre for Mental Health Services Development, Queen Mary University of London, London, UK 2 Institute of Psychiatry, Psychology and Neuroscience, King s College London, London, UK 3 Department of Psychiatry, University of Liverpool, Liverpool, UK 4 Services Psychiatriques Jura bernois, Bienne-Seeland, Bellelay, Switzerland 5 Department of Psychiatry and Psychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands 6 Centre for the Economics of Mental and Physical Health, Institute of Psychiatry, Psychology and Neuroscience, King s College London, London, UK 7 Division of Primary Care and Public Health, Brighton and Sussex Medical School, Brighton, UK 8 Centre for Primary Care and Public Health, Queen Mary University of London, London, UK *Corresponding author s.priebe@qmul.ac.uk Background: The negative symptoms of schizophrenia significantly impact on quality of life and social functioning, and current treatment options are limited. In this study the clinical effectiveness and cost-effectiveness of group body psychotherapy as a treatment for negative symptoms were compared with an active control. Design: A parallel-arm, multisite randomised controlled trial. Randomisation was conducted independently of the research team, using a 1 : 1 computer-generated sequence. Assessors and statisticians were blinded to treatment allocation. Analysis was conducted following the intention-to-treat principle. In the cost-effectiveness analysis, a health and social care perspective was adopted. Participants: Eligibility criteria: age years; diagnosis of schizophrenia with symptoms present at > 6 months; score of 18 on Positive and Negative Syndrome Scale (PANSS) negative symptoms subscale; no change in medication type in past 6 weeks; willingness to participate; ability to give informed consent; and community outpatient. Exclusion criteria: inability to participate in the groups and insufficient command of English. Settings: Participants were recruited from NHS mental health community services in five different Trusts. All groups took place in local community spaces. Interventions: Control intervention: a 10-week, 90-minute, 20-session group beginners Pilates class, run by a qualified Pilates instructor. Treatment intervention: a 10-week, 90-minute, 20-session manualised group body psychotherapy group, run by a qualified dance movement psychotherapist. Queen s Printer and Controller of HMSO This work was produced by Priebe et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. vii

11 ABSTRACT Outcomes: The primary outcome was the PANSS negative symptoms subscale score at end of treatment. Secondary outcomes included measures of psychopathology, functional, social, service use and treatment satisfaction outcomes, both at treatment end and at 6-month follow-up. Results: A total of 275 participants were randomised (140 body psychotherapy group, 135 Pilates group). At the end of treatment, 264 participants were assessed (137 body psychotherapy group, 127 Pilates group). The adjusted difference in means of the PANSS negative subscale at the end of treatment was 0.03 [95% confidence interval (CI) 1.11 to 1.17], showing no advantage of the intervention. In the secondary outcomes, the mean difference in the Clinical Assessment Interview for negative symptoms expression subscale at the end of treatment was 0.62 (95% CI 1.23 to 0.00), and in extrapyramidal movement disorder symptoms 0.65 (95% CI 1.13 to 0.16) at the end of treatment and 0.58 (95% CI 1.07 to 0.09) at 6 months follow-up, showing a small significant advantage of body psychotherapy. No serious adverse events related to the interventions were reported. The total costs of the intervention were comparable with the control, with no clear evidence of cost-effectiveness for either condition. Limitations: Owing to the absence of a treatment-as-usual arm, it is difficult to determine whether or not both arms are an improvement over routine care. Conclusions: In comparison with an active control, group body psychotherapy does not have a clinically relevant beneficial effect in the treatment of patients with negative symptoms of schizophrenia. These findings conflict with the review that led to the current National Institute for Health and Care Excellence guidelines suggesting that arts therapies may be an effective treatment for negative symptoms. Future work: Determining whether or not this lack of effectiveness extends to all types of art therapies would be informative. Trial registration: Current Controlled Trials ISRCTN Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 11. See the NIHR Journals Library website for further project information. viii NIHR Journals Library

12 DOI: /hta20110 HEALTH TECHNOLOGY ASSESSMENT 2016 VOL. 20 NO. 11 Contents List of tables List of figures List of abbreviations Plain English summary Scientific summary xi xiii xv xvii xix Chapter 1 Background 1 Schizophrenia and negative symptoms 1 Schizophrenia and arts therapies 1 Body psychotherapy and schizophrenia 2 Theoretical basis for body psychotherapy as a treatment for schizophrenia 2 Features of the body psychotherapy treatment 3 Effects of physical activity in schizophrenia 3 Aims and objectives 4 Chapter 2 Methods 5 Design 5 Amendments to the protocol 5 Amendment 1 5 Amendment 2 5 Amendment 3 5 Amendment 4 5 Amendment 5 5 Eligibility criteria 6 Inclusion criteria 6 Exclusion criteria 6 Outcome measures 6 Blinding and randomisation 9 Procedures 9 Treatment and control conditions 10 Treatment condition 10 Control condition 11 Sample size calculation 12 Analysis plan 12 Economic analysis plan 13 Ethical considerations 13 Patient and Public Involvement 14 Chapter 3 Results 15 Participant recruitment and retention 15 Baseline characteristics 17 Uptake of interventions 18 Therapist adherence to manual 19 Primary outcome 19 Queen s Printer and Controller of HMSO This work was produced by Priebe et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. ix

13 CONTENTS Secondary outcomes 19 Ancillary analyses 22 Analysis following imputation 22 Complier-average causal effect analysis 23 Subgroup analysis 24 Adverse events 26 Economic analysis 26 Service use 26 Assessment of quality-adjusted life-years 29 Cost utility analysis 29 Cost-effectiveness of improving negative symptoms 29 Chapter 4 Discussion 33 Study findings 33 Interpretation 33 Generalisability 35 Chapter 5 Conclusions 37 Implications for health care 37 Recommendations for research 38 Other information 38 Protocol 38 Acknowledgements 39 References 41 Appendix 1 Body psychotherapy session sheet 45 Appendix 2 Body Psychotherapy Adherence Scale 49 Appendix 3 Pilates guide 51 Appendix 4 Client report file 55 x NIHR Journals Library

14 DOI: /hta20110 HEALTH TECHNOLOGY ASSESSMENT 2016 VOL. 20 NO. 11 List of tables TABLE 1 Descriptive statistics of participant characteristics at baseline, for experimental and control conditions 17 TABLE 2 Baseline outcome measures of the study sample 18 TABLE 3 Number of sessions attended by those randomised to a group 19 TABLE 4 Outcomes at end of treatment and 6-month follow-up in the BPT and Pilates groups, using an available case analysis 20 TABLE 5 Adjusted differences in means between the groups at end of treatment and 6-month follow-up, using the imputed data sets (intention-to-treat analysis) 22 TABLE 6 Complier-average causal effect analysis estimates, using a minimum of 5 and 10 sessions of BPT attendance as an indicator of compliance 23 TABLE 7 Numbers and proportions in each subgroup category for the PANSS, CAINS scale and Calgary Depression Scale 24 TABLE 8 Difference in treatment response between those with high ( 23) and low (< 23) negative symptoms as measured with the PANSS negative subscale 25 TABLE 9 Difference in treatment response between those with long (> 5 years) and short ( 5 years) illness duration 25 TABLE 10 Difference in treatment response between those with long (> 15 years) and short ( 15 years) illness duration 26 TABLE 11 Number of participants using services and their volume of use 27 TABLE 12 Cost of services use (excluding intervention) prior to baseline and follow-up assessments (2013/14, ) 28 TABLE 13 Differences in incremental costs, effects and cost-effectiveness at 6 months follow-up 29 Queen s Printer and Controller of HMSO This work was produced by Priebe et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xi

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16 DOI: /hta20110 HEALTH TECHNOLOGY ASSESSMENT 2016 VOL. 20 NO. 11 List of figures FIGURE 1 Consolidated Standards of Reporting Trials (CONSORT) diagram 16 FIGURE 2 Cost-effectiveness plane of 1000 bootstrap-replicated ICERs for BPT compared with Pilates, based on health and social care costs and QALYs over 6 months, adjusted for baseline costs and utility 30 FIGURE 3 Cost-effectiveness acceptability curve indicating the probability that BPT is cost-effective compared with Pilates, base on health and social care costs and QALYs over 6 months 30 FIGURE 4 Cost-effectiveness plane of 1000 bootstrap-replicated ICERs for BPT compared with Pilates, based on health and social care costs and negative symptom change over 6 months, adjusted for baseline costs and PANSS negative subscale score 31 Queen s Printer and Controller of HMSO This work was produced by Priebe et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xiii

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18 DOI: /hta20110 HEALTH TECHNOLOGY ASSESSMENT 2016 VOL. 20 NO. 11 List of abbreviations ADMP BPT CACE Association of Dance Movement Psychotherapy body psychotherapy complier-average causal effect ICER IQR ISRCTN incremental cost-effectiveness ratio interquartile range International Standard Randomised Controlled Trial Number CAINS Clinical Assessment Interview for Negative Symptoms MANSA Manchester Short Assessment of Quality of Life CEAC CEP CI CONSORT CRF CSQ CSRI CTU DMEC EPS EQ-5D cost-effectiveness acceptability curve cost-effectiveness plane confidence interval Consolidated Standards of Reporting Trials case report file Client Satisfaction Questionnaire Client Service Receipt Inventory Clinical Trials Unit Data Monitoring and Ethics Committee extrapyramidal side effect European Quality of Life-5 Dimensions MATISSE NICE PANSS PCTU QALY RCT REC REPS SANS SAS SD Multicentre evaluation of Art Therapy In Schizophrenia: Systematic Evaluation National Institute for Health and Care Excellence Positive and Negative Syndrome Scale Pragmatic Clinical Trials Unit quality-adjusted life-year randomised controlled trial Research Ethics Committee Register of Exercise Professionals Scale to Assess Negative Symptoms Simpson Angus Scale standard deviation EQ-5D-5L GP ICC ICD-10 European Quality of Life-5 Dimensions, five-level version general practitioner intraclass correlation coefficient International Classification of Diseases, Tenth Edition SNS TAS TSC TUS Social Network Scale Toronto Alexithymia Scale Trial Steering Committee Time Use Survey Queen s Printer and Controller of HMSO This work was produced by Priebe et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xv

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20 DOI: /hta20110 HEALTH TECHNOLOGY ASSESSMENT 2016 VOL. 20 NO. 11 Plain English summary Symptoms of schizophrenia, such as reduced emotions and lack of drive, can reduce a person s quality of life. At present, there are few treatment options that have been found to help. Arts therapies (which involve different, more creative ways to help people communicate than just talking) may be helpful, but more evidence is needed. One form of art therapy is body psychotherapy, which uses movement and the body as a form of treatment. In a recent small study, body psychotherapy was found to reduce symptoms, but it is not clear if it is the group activity or the therapy itself that caused the improvement, or if the improvement would still occur if the treatment was conducted at different sites by different therapists. In this study, 275 people were randomised to take part in a 20-session body psychotherapy group or a 20-session Pilates class. Symptoms, the cost of health services used and measurements of well-being were taken before the first group session, after the last session and then again 6 months later. The measurements from the participants who were offered the body psychotherapy group were then compared with those who were offered the Pilates class. In both groups only very small improvements in symptoms were found, which means that the body psychotherapy group did not improve symptoms more than Pilates. These findings appear to contradict the current guidelines, which suggest that art therapies may be helpful in addressing a lack of drive and reduced emotions. Queen s Printer and Controller of HMSO This work was produced by Priebe et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xvii

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22 DOI: /hta20110 HEALTH TECHNOLOGY ASSESSMENT 2016 VOL. 20 NO. 11 Scientific summary Background The negative symptoms of schizophrenia refer to expressive deficits, such as impoverished speech and blunted affect, and experiential/pleasure deficits, such as anhedonia, avolition and asociality. These negative symptoms have been found to be largely resistant to antipsychotic medication and conventional psychotherapeutic interventions, and significantly impact on quality of life and social functioning. There is some evidence to suggest that arts therapies could be effective in the treatment of these symptoms; however, the current data are limited and full-scale trials are required. In a review by the National Institute for Health and Care Excellence (NICE), arts therapies which is a label covering all creative therapies, such as music therapy, art therapy, body psychotherapy (BPT), dance movement psychotherapy and drama therapy were the only type of intervention found to demonstrate consistent efficacy in the amelioration of negative symptoms. However, given that the findings were based on only six small-scale studies, the recommendations for further research recognised the need for larger trials. In addition, it was recommended that trials include an active control group in order to control for any non-specific effects of taking part in group activities. The aim of this trial is to assess the clinical effectiveness and cost-effectiveness of a manualised form of group BPT that was designed to treat the negative symptoms of schizophrenia in outpatients, comparing outcomes with those from outpatients attending Pilates classes. Pilates is a type of structured physical fitness programme involving stretching and controlled movement, which will control for the effects of therapist attention and group-structured physical activity. In comparing BPT with a physically active control, the aim of the trial was to evaluate the specific components of BPT, which includes the focus on body experience at a cognitive and emotional level, the facilitation of emotional group interactions and the link between movement and emotion. Objectives The objectives were to: 1. test the effectiveness of a manualised group BPT intervention in reducing negative symptoms of schizophrenia compared with an active control 2. test the effectiveness of a manualised group BPT intervention in general psychopathology, quality of life, daily activities, objective social situation and treatment satisfaction in participants who were experiencing negative symptoms of schizophrenia compared with an active control 3. test whether or not any effects on primary and secondary outcomes are maintained at 6 months follow-up 4. assess the cost impact, cost-effectiveness and cost utility of BPT. Queen s Printer and Controller of HMSO This work was produced by Priebe et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xix

23 SCIENTIFIC SUMMARY Method The study was a two-arm, parallel-group, multisite randomised controlled trial (RCT). Patients with schizophrenia [International Classification of Diseases, Tenth Edition (ICD-10) codes F20.0 F20.9] experiencing at least moderate levels of negative symptoms [score of 18 on the Positive And Negative Syndrome Scale (PANSS) negative subscale] were randomised into a 20-session (10-week) BPT group, or a 20-session (10-week) Pilates class. Randomisation was conducted by a statistician from the Clinical Trials Unit through a computer-generated sequence. Participants were randomly allocated, with equal probability, to the intervention or control group, stratified by study centre, in batches using randomly permuted blocks of 4 and 6, starting each batch at the start of a new block in order to preserve balance. Assessors and statisticians were blinded to treatment allocation until the analysis plan was signed off. Analysis was conducted following intention-to-treat principles. Participants Participants were recruited from the UK NHS mental health community services in five different Trusts. The eligibility criteria included ages years; ICD-10 diagnosis of schizophrenia, with symptoms present for at least 6 months; score of 18 on PANSS negative symptoms subscale; no change in medication type in the past 6 weeks; willingness to participate; ability to give informed consent; and community outpatient. The exclusion criteria included inability to participate in the groups because of physical disability or condition and insufficient command of English. All groups took place in local community spaces. Procedures Potentially eligible participants were approached by their clinicians for their consent to be contacted by a researcher. If they agreed, the researcher arranged a meeting during which a detailed explanation of the study was provided, and, presuming that they were interested in taking part, informed consent was obtained. An eligibility assessment using the PANSS scale was then conducted to ascertain whether or not they had a rating of at least 18 on the negative symptoms subscale, in accordance with the inclusion criterion. Once approximately 16 eligible participants at each site were recruited, a full baseline assessment which included a second PANSS assessment was undertaken 1 month prior to the group start date. The assessments were typically conducted in the participants homes or at their local community mental health team base. On completion of the groups, the researchers contacted the participants again for the end-of-treatment assessment, which included all of the structured interviews and questionnaires obtained in the baseline assessment, in addition to the Client Satisfaction Questionnaire (CSQ) which was used to measure the participants satisfaction with treatment. Six months after intervention completion, patients were contacted a final time to arrange the follow-up assessment, which, again, included all of the interviews and questionnaires of the baseline assessment. The treatment under investigation was BPT, as outlined in an updated version of the manual used in the 2006 exploratory trial. Both BPT and the Pilates groups were delivered twice per week on non-consecutive days for 10 weeks, with each session lasting 90 minutes. A maximum of 10 participants were assigned to each group or class. To limit the impact of any one body psychotherapist or Pilates instructor on outcomes, each one was permitted to run a maximum of two groups. The BPT group was facilitated by an Association of Dance Movement Psychotherapy (ADMP) accredited therapist, who had attended an additional 2-day training course in delivering the intervention in its manualised form. In each group, the therapist was supported by a volunteer as cofacilitator. Each therapist received a minimum of three 90-minute supervision sessions held by a senior therapist for each group, either in person or via a videoconference. xx NIHR Journals Library

24 DOI: /hta20110 HEALTH TECHNOLOGY ASSESSMENT 2016 VOL. 20 NO. 11 Each of the 20 sessions comprised five discrete sections. The first was the opening circle, which is used to describe feelings and energy levels; the second was a warm-up section, for which the participants stand in a circle and warm up using different body parts and movements; the third was a structured task section with exercises, such as mirroring each other s movements and creating body image sculpture in partners; the fourth consisted of creative movements, with exercises such as creating group sculptures and reflecting on perceptions and emotions; and finally, the fifth was a closing circle, which was used to reflect on the group experience and to refocus on the self with body-orientated exercises. The Pilates classes were held in the same venues as the BPT groups. All classes were facilitated by a Register of Exercise Professionals (REPS) level 3-qualified Pilates instructor, and assisted by a cofacilitator. Prior to the classes starting, a brief training session was arranged between the instructor and an experienced clinician. Outcomes The primary outcome was the PANSS negative symptoms subscale score, which was assessed at the end of treatment. Secondary outcomes included the PANSS negative subscale score at 6 months post treatment, in addition to general psychopathology and positive symptoms (PANSS), subjective quality of life (Manchester Short Assessment of Quality of Life; MANSA), level of activity (items from the Time Use Survey; TUS), objective social situation (SIX), extrapyramidal symptoms resulting from antipsychotic medication (Simpson Angus Scale; SAS), emotional experience and expression (Clinical Assessment Interview for Negative Symptoms; CAINS), depression (Calgary Depression Scale) and social contacts (Social Network Scale; SNS), measured both at end of treatment and at 6 months follow-up. Satisfaction of treatment was measured at the end of the treatment phase (Client Satisfaction Questionnaire; CSQ). In addition, cost impact, cost-effectiveness and cost utility were assessed using the European Quality of Life-5 Dimensions (EQ-5D) and the Client Service Receipt Inventory (CSRI). Statistical methods A 20% reduction in the PANSS score was used as an indicator of clinically significant improvement, which would be a difference of approximately 3 points, given the eligibility criteria. To detect this difference with a standard deviation (SD) of 5, with 90% power for 5% significance, 58 patients were required in each arm. To allow for clustering by group, an intraclass correlation coefficient (ICC) for treatment group of 0.1, and seven patients per group with analysable data at the end of treatment, gives an inflation factor of 1.6, meaning that 93 participants in each arm were required. At 6 months we anticipated a loss to follow-up of 31%, so recruiting 256 participants would leave 88 per arm at 6 months, and 91% power to detect a difference of 3 points at this time point. The primary analysis was of available cases of the PANSS negative subscale at end of treatment, following intention-to-treat principles. We used a mixed-effects model, fitted by restricted maximum likelihood with fixed effects for the intervention, baseline PANSS negative subscale scores, and centre (because it was used to stratify the randomisation), and random effects for therapy groups to allow for clustering by group. Secondary outcomes were analysed using the same approach. To evaluate the impact of missing data, multiple imputation of the data set was performed and the analysis was replicated. A simple complier-average causal effect analysis (CACE) was completed. In this analysis, compliance was defined as attending at least five sessions, following the results of a recent study that evaluated the effectiveness of BPT for chronic depression. Planned subgroup analyses examining whether or not there were differences in response between those with higher negative symptoms at baseline and a longer duration of illness were also conducted. All analyses were completed using Stata version 12 (StataCorp LP, College Station, TX, USA). Queen s Printer and Controller of HMSO This work was produced by Priebe et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xxi

25 SCIENTIFIC SUMMARY Results In total, 275 participants were randomised: 140 to the BPT group and 135 to the Pilates group. Each group comprised between 7 and 10 participants. Attendance was relatively high in both groups; however, participants attended significantly more sessions in the BPT arm than in Pilates group [BPT median = 11, interquartile range (IQR) = 5 17; Pilates median = 8, IQR = 1 15; p = 0.01]. In the BPT arm, 106 participants (75.7%) attended at least 5 of the 20 sessions, thus fulfilling the minimum attendance threshold required to be defined as a treatment complier in the CACE analysis. In the primary outcome, no significant difference between the experimental and control condition was detected [adjusted difference in the means = 0.03, 95% confidence interval (CI) 1.11 to 1.17; p = 0.959, model-based ICC = after controlling for baseline scores, study centre and therapy group]. In the secondary outcomes at the end of treatment, a significant mean difference reduction in the SAS ( 0.65, 95% CI 1.13 to 0.16; p = 0.009, ICC < 0.001) and the CAINS expression subscale ( 0.62, 95% CI 1.23 to 0.00; p = 0.049, ICC = 0.022) was detected in favour of the BPT arm in comparison with the Pilates group at the end of treatment. No other significant differences were found in the secondary outcomes at this stage. At the 6-month follow-up, a significant mean difference in the SAS was detected ( 0.50, 95% CI 0.97 to 0.07; p = 0.028, ICC < 0.001); however, no other differences were detected. In the CACE analysis, a significant difference was found in the SAS at end of treatment ( 0.82, 95% CI 1.51 to 0.12); however, no other differences were detected, including in the primary outcome of negative symptoms. No significant differences in negative symptoms were detected in the subgroup analysis, which compared those with high and low negative symptoms, and long and short duration of illness. There were no serious adverse events related to the intervention. The total mean costs per participant in the BPT over the whole follow-up period were 2297 (SD = 2835) in comparison with 2442 (SD = 3278) for Pilates. After adjusting for baseline, the total costs were slightly lower for BPT; however, the difference was non-significant ( 25; bootstrapped 95% CI 671 to 721). No significant differences were detected in the sensitivity analysis, for which the costs of Pilates were changed to zero ( 55, 95% CI 630 to 706). No significant differences were detected in quality-adjusted life-years (QALYs) between BPT and Pilates (adjusted difference in means = 0.01; 95% CI 0.02 to 0.04). At 20,000 per QALY, it was found that there is approximately a 65% likelihood that BPT is a more cost-effective option than Pilates. Conclusions No significant differences between BPT and Pilates were detected in the PANSS negative symptoms subscale, both at the end of treatment and 6 months later. A statistically significant improvement in the BPT group in comparison with the Pilates group was detected in the CAINS expression subscale at the end of treatment, and, in movement disorder symptoms, both at end of treatment and 6 months later. However, the small effect sizes mean these are unlikely to reflect relevant clinical benefits. There was no significant difference on any other outcome. Given the results and the high statistical power, these findings support the conclusion that BPT is not an effective treatment for patients with negative symptoms of schizophrenia compared with Pilates as an active control. xxii NIHR Journals Library

26 DOI: /hta20110 HEALTH TECHNOLOGY ASSESSMENT 2016 VOL. 20 NO. 11 Implications for health care In comparison with an active control, group BPT does not have a clinically relevant beneficial effect in the treatment of patients with negative symptoms of schizophrenia. These results are consistent with an earlier RCT [Multicenter evaluation of Art Therapy in Schizophrenia: Systematic Evaluation (MATISSE)] evaluating the effectiveness of art therapy as a treatment for schizophrenia and, together, contradict current NICE guidelines, which suggest that arts therapies are an effective treatment for negative symptoms. Trial registration This trial is registered as ISRCTN Funding Funding for this study was provided by the Health Technology Assessment programme of the National Institute for Health Research. Queen s Printer and Controller of HMSO This work was produced by Priebe et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xxiii

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28 DOI: /hta20110 HEALTH TECHNOLOGY ASSESSMENT 2016 VOL. 20 NO. 11 Chapter 1 Background Schizophrenia and negative symptoms Schizophrenia is a severely disabling mental health disorder that affects approximately 0.7% of the population. 1 The main symptoms are commonly characterised into positive symptoms, which include hallucinations, disordered thinking and delusions, and negative symptoms, which refer to deficits in emotional experience and expression. Specific symptoms relating to emotional expression include blunted affect and alogia (impoverished speech), whereas deficits in emotional experience can include asociality, anhedonia (inability to anticipate or experience pleasure) and amotivation. 2 Negative symptoms have been found to be highly detrimental to social outcomes, quality of life and functioning, 3,4 and so are important targets for treatment. However, despite developments in both antipsychotic medication and psychological treatments, the effectiveness of most treatments on negative symptoms has been found to be limited. 5 This being the case, the negative symptoms are currently recognised as an unmet therapeutic need in a large proportion of cases. 5 Schizophrenia and arts therapies Arts therapies is an umbrella term for a range of different therapies, which include music therapy, art therapy, body psychotherapy (BPT), dance movement psychotherapy and drama therapy. Common to all of them is that they have a central non-verbal component, with the focus on utilising creative activities to achieve psychological change. In a review on treatment strategies in schizophrenia by the National Institute for Health and Care Excellence (NICE), arts therapies were found to be the only type of treatment to demonstrate clear, consistent improvement in negative symptoms; 6,7 however, the sample size for the meta-analysis was small (six trials, n = 382), leading to the suggestion that the evidence base should be increased with more large-scale trials of arts therapies. Furthermore, none of the studies compared the intervention with an active control, so it remains unclear whether it is the specific effects of the psychotherapeutic component of arts therapies or the non-specific effects of regular group activity that are driving the changes. Finally, no studies evaluating evidence on the cost-effectiveness of such interventions were identified. Consequently, the research recommendations suggested that further trials should be conducted to test the clinical effectiveness and cost-effectiveness of arts therapies for patients with schizophrenia, that such trials should be sufficiently powered and that they should use an active control. Since the recommendations were published, a full-scale, multicentre randomised controlled trial (RCT) evaluating the effectiveness of art therapy has been completed [Multicenter evaluation of Art Therapy in Schizophrenia: Systematic Evaluation (MATISSE)]. 8 In this study, no significant improvements in either negative symptoms or any of the secondary outcomes were found in the art therapy group, relative to either the active control group or standard care. The MATISSE trial 8 was designed as a pragmatic trial with the aim of testing the impact of group art therapy delivered in current clinical practice, meaning that one specific model of therapy was not evaluated. Consequently, the type of treatment provided was not consistently applied, which has been criticised by some art therapists, who have suggested that what was evaluated is not what is routinely delivered in the UK. 9,10 In response to this critique, the MATISSE study team have since published a more comprehensive description of the therapy delivered, 11 which contends that such a method of implementation is consistent with the principles of pragmatic trials. Regardless, new trials of arts therapies that implement a standardised therapy, recognised as appropriate for the patient group beforehand, would be a significant advance in the evidence base. Queen s Printer and Controller of HMSO This work was produced by Priebe et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. 1